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A noise attenuation performance test was conducted on earmuffs using a recoilless weapon launch platform in a confined space, along with two acoustic test fixtures (ATFs). The overpressure at the ATF's effective tympanic membrane comprised direct sound at 185 dB sound pressure level (SPL) and reflected sound at 179 dB SPL. Wearing earmuffs reduced these peaks to 162 dB SPL and 169 dB SPL, respectively. The reflected sound from walls was defined as delayed sound. An analytical model for earmuff noise attenuation simulated their effectiveness. The simulation revealed that when the earmuffs attenuated delayed sound, the acoustic impedance of acoustic leakage and the acoustic impedance of the earmuff material decreased by 96% and 50%, respectively. The negative overpressure zone between direct and delayed sound decreased the earmuffs' fit against the ATF. Additionally, the enclosed volume between the earmuff and the ear canal decreased by 12%. After the installation of bandages on the earmuffs, the overpressure peak of delayed sound was reduced by 5 dB. Furthermore, the acoustic impedance of the earmuff's sound leakage path and the acoustic impedance of the earmuff material deformation path increased by 100% and 809%, respectively.
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Acústica , Dispositivos de Protección de los Oídos , Presión , Humanos , Diseño de Equipo , Ruido , Sonido , Armas de Fuego , Adulto , Masculino , Factores de Tiempo , Modelos TeóricosRESUMEN
A novel axially chiral all-hydrocarbon cyclo[7] (1,3-(4,6-dimethyl)benzene (CDMB-7) was designed and synthesized using atroposelective[2 + 5] cyclization through Suzuki-Miyaura coupling. CDMB-7 adopts an irregular bowl-like shape with C2 symmetry and exhibits two diastereoisomers in its crystallographic structure. The conformational isomers of CDMB-7 racemates remain stable at high temperatures (393 K). High-performance liquid chromatography (HPLC) confirmed that a single chiral isomer will spontaneously undergo racemization within 30 min at room temperature. This finding opens up possibilities for achieving adaptive chirality in all-hydrocarbon cyclo[7] m-benzene macrocycles.
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In diabetic patients with skin injuries, bacterial proliferation, accumulation of reactive oxygen species (ROS) in the tissues, and impaired angiogenesis make wound healing difficult. Therefore, eliminating bacteria, removing ROS, and promoting angiogenesis are necessary for treating acute diabetic wounds. In this study, benefiting from the ability of polyphenols to form a metal-phenolic network (MPN) with metal ions, TA-Eu MPN nanoparticles (TM NPs) were synthesized. The prepared photothermal agent CuS NPs and TM NPs were then loaded onto the supporting base and needle tips of PVA/HA (PH) microneedles, respectively, to obtain PH/CuS/TM microneedles. Antibacterial experiments showed that microneedles loaded with CuS NPs could remove bacteria by the photothermal effect. In vitro experiments showed that the microneedles could effectively scavenge ROS, inhibit macrophage polarization to the M1 type, and induce polarization to the M2 type as well as have the ability to promote vascular endothelial cell migration and angiogenesis. Furthermore, in vivo experiments showed that PH/CuS/TM microneedles accelerated wound healing by inhibiting pro-inflammatory cytokines and promoting angiogenesis in a diabetic rat wound model. Therefore, PH/CuS/TM microneedles have efficient antibacterial, ROS scavenging, anti-inflammatory, immunomodulatory, and angiogenic abilities and hold promise as wound dressings for treating acute diabetic wounds.
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Antibacterianos , Diabetes Mellitus Experimental , Especies Reactivas de Oxígeno , Cicatrización de Heridas , Cicatrización de Heridas/efectos de los fármacos , Animales , Especies Reactivas de Oxígeno/metabolismo , Ratas , Antibacterianos/farmacología , Antibacterianos/química , Diabetes Mellitus Experimental/tratamiento farmacológico , Ratones , Neovascularización Fisiológica/efectos de los fármacos , Agujas , Ratas Sprague-Dawley , Humanos , Masculino , Células Endoteliales de la Vena Umbilical Humana , Depuradores de Radicales Libres/química , Depuradores de Radicales Libres/farmacología , Células RAW 264.7 , AngiogénesisRESUMEN
Background: Platinum-based chemotherapy combined with immune checkpoint inhibitors (ICIs) is now becoming the standard first-line therapy for human epidermal growth factor receptor 2 (HER2)-negative advanced gastric cancer (AGC). In China, paclitaxel has shown good efficacy and tolerability in AGC as an alternative for first-line therapy. Combining ICIs with paclitaxel-based chemotherapy may lead to improved tumor immune microenvironment, but evidence in paclitaxel combing with ICIs as first-line regimen is lacking. This multicenter, retrospective research aims to compare effectiveness and tolerability of paclitaxel-based chemotherapy combined with ICIs versus chemotherapy alone as a first-line treatment of HER2-negative AGC in a real-world setting. Methods: Eighty-six patients with HER2-negative AGC were included from 2017 to 2022. Among them, 57 patients received paclitaxel-based chemotherapy plus ICIs, and 29 patients received paclitaxel-based chemotherapy alone. We compared the efficacy and incidence of adverse events between the two therapy options. Results: Significant improvements in median progression-free survival (PFS) (8.77 versus 7.47 months; P=0.04) and median overall survival (OS) (15.70 versus 14.33 months; P=0.04) were observed in the ICIs combined with paclitaxel-based chemotherapy group. The use of ICIs also significantly prolonged the duration of response (DOR) (7.47 versus 4.59 months; P=0.02). Meanwhile, the ICIs plus chemotherapy group demonstrated significantly improved objective response rate (ORR) (50.9% vs. 27.6%; P=0.03) and disease control rate (DCR) (98.3% vs. 82.8%; P=0.01), and the side effects were tolerable. Conclusions: In summary, for HER2-negative AGC, ICIs plus paclitaxel-based chemotherapy is effective with mild toxicities, which should be considered as an alternative first-line therapy regimen.
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Bone defects caused by trauma, tumor resection, or developmental abnormalities are important issues in clinical practice. The vigorous development of tissue engineering technology provides new ideas and directions for regenerating bone defects. Hydroxyapatite (HAp), a bioactive ceramic, is extensively used in bone tissue engineering because of its excellent osteoinductive performance. However, its application is challenged by its single function and conventional environment-unfriendly synthesis methods. In this study, we successfully "green" synthesized sr-silk fibroin co-assembly hydroxyapatite nanoparticles (Sr-SF-HA) using silk fibroin (SF) as a biomineralized template, thus enabling it to have angiogenic activity and achieving the combination of organic and inorganic substances. Then, the rough composite microspheres loaded with Sr-SF-HA (CS/Sr-SF-HA) through electrostatic spraying technology and freeze-drying method were prepared. The CCK-8 test and live/dead cell staining showed excellent biocompatibility of CS/Sr-SF-HA. Alkaline phosphatase (ALP) staining, alizarin red staining (ARS), immunofluorescence, western blotting, and qRT-PCR test showed that CS/Sr-SF-HA activated the expression of related genes and proteins, thus inducing the osteogenic differentiation of rBMSCs. Moreover, tube formation experiments, scratch experiments, immunofluorescence, and qRT-PCR detection indicated that CS/Sr-SF-HA have good angiogenic activity. Furthermore, in vivo studies showed that the CS/Sr-SF-HA possesses excellent biocompatibility, vascular activity, as well as ectopic osteogenic ability in the subcutaneous pocket of rats. This study indicates that the construction of CS/Sr-SF-HA with angiogenic and osteogenic properties has great potential for bone tissue engineering.
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The banana Fusarium wilt (BFW) caused by Fusarium oxysporum f. sp. cubense tropical race4 (FocTR4) is difficult to control worldwide, which causes a huge economic losse to banana industry. The purpose of this study was to screen Trichoderma strains with antagonistic activity against FocTR4, to isolate and purify the active compound from the fermentation broth, so as to provide important biocontrol strains and active compound resources. In this work, Trichoderma strains were isolated and screened from the rhizosphere soil of crops, and the strains capable of efficiently inhibiting FocTR4 were screened by plate confrontation, and further confirmed by testing inhibition for the conidial germination and mycelial growth of FocTR4. The phylogenetic tree clarified the taxonomic status of the biocontrol strains. Moreover, the active components in the fermentation broth of the strains were separated and purified by column chromatography, the structure of the most active component was analyzed by nuclear magnetic resonance spectroscopy (NMR), the BFW control effect was tested by pot experiments. We obtained a strain JSHA-CD-1003 with antagonistic activity against FocTR4, and the inhibition rate from plate confrontation was 60.6%. The fermentation broth of JSHA-CD-1003 completely inhibited the germination of FocTR4 conidia within 24 hours. The inhibition rate of FocTR4 hyphae growth was 52.6% within 7 d. A phylogenetic tree was constructed based on the ITS and tef1-α gene tandem sequences, and JSHA-CD-1003 was identified as Trichoderma brevicompactum. Purification and NMR identification showed that the single active compound was trichodermin, and the minimum inhibitory concentration (MIC) was 25 µg/mL. Pot experiments showed that the fermentation broth of strain JSHA-CD-1003 was effective against BFW. The control rate of leaf yellowing was 47.4%, and the rate of bulb browning was 52.0%. Therefore, JSHA-CD-1003 effectively inhibited FocTR4 conidial germination and mycelium growth through producing trichodermin, and showed biocontrol effect on banana wilt caused by FocTR4, thus is a potential biocontrol strain.
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Fusarium , Hypocreales , Musa , Filogenia , TricoderminaRESUMEN
Accumulation of reactive oxygen species (ROS) in periodontitis exacerbates the destruction of alveolar bone. Therefore, scavenging ROS to reshape the periodontal microenvironment, alleviate the inflammatory response and promote endogenous stem cell osteogenic differentiation may be an effective strategy for treating bone resorption in periodontitis. In this study, sericin-hydroxyapatite nanoparticles (Se-nHA NPs) are synthesized using a biomimetic mineralization method. Se-nHA NPs and proanthocyanidins (PC) are then encapsulated in sericin/sodium alginate (Se/SA) using an electrostatic injection technique to prepare Se-nHA/PC microspheres. Microspheres are effective in scavenging ROS, inhibiting the polarization of macrophages toward the M1 type, and inducing the polarization of macrophages toward the M2 type. In normal or macrophage-conditioned media, the Se-nHA/PC microspheres effectively promoted the osteogenic differentiation of human periodontal ligament stem cells (hPDLSCs). Furthermore, the Se-nHA/PC microspheres demonstrated anti-inflammatory effects in a periodontitis rat model by scavenging ROS and suppressing pro-inflammatory cytokines. The Se-nHA/PC microspheres are also distinguished by their capacity to decrease alveolar bone loss, reduce osteoclast activity, and boost osteogenic factor expression. Therefore, the biomimetic Se-nHA/PC composite microspheres have efficient ROS-scavenging, anti-inflammatory, and osteogenic abilities and can be used as a multifunctional filling material for inflammatory periodontal tissue regeneration.
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Periodontitis , Proantocianidinas , Sericinas , Humanos , Animales , Ratas , Osteogénesis , Biomimética , Microesferas , Especies Reactivas de Oxígeno , Regeneración Ósea , Periodontitis/terapia , Durapatita , AntiinflamatoriosRESUMEN
The chemokine receptor CXCR3 is functionally pleiotropic, not only recruiting immune cells to the inflamed liver but also mediating the pathological process of cholestatic liver injury (CLI). However, the mechanism of its involvement in the CLI remains unclear. Both alpha-naphthylisothiocyanate (ANIT) and triptolide are hepatotoxicants that induce CLI by bile acid (BA) dysregulation, inflammation, and endoplasmic reticulum (ER)/oxidative stress. Through molecular docking, CXCR3 is a potential target of ANIT and triptolide. Therefore, this study aimed to investigate the role of CXCR3 in ANIT- and triptolide-induced CLI and to explore the underlying mechanisms. Wild-type mice and CXCR3-deficient mice were administered with ANIT or triptolide to compare CLI, BA profile, hepatic recruitment of IFN-γ/IL-4/IL-17+CD4+T cells, IFN-γ/IL-4/IL-17+iNKT cells and IFN-γ/IL-4+NK cells, and the expression of ER/oxidative stress pathway. The results showed that CXCR3 deficiency ameliorated ANIT- and triptolide-induced CLI. CXCR3 deficiency alleviated ANIT-induced dysregulated BA metabolism, which decreased the recruitment of IFN-γ+NK cells and IL-4+NK cells to the liver and inhibited ER stress. After triptolide administration, CXCR3 deficiency ameliorated dysregulation of BA metabolism, which reduced the migration of IL-4+iNKT cells and IL-17+iNKT cells and reduced oxidative stress through inhibition of Egr1 expression and AKT phosphorylation. Our findings suggest a detrimental role of CXCR3 in ANIT- and triptolide-induced CLI, providing a promising therapeutic target and introducing novel mechanisms for understanding cholestatic liver diseases.
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1-Naftilisotiocianato , Colestasis , Diterpenos , Fenantrenos , Animales , Ratones , 1-Naftilisotiocianato/toxicidad , 1-Naftilisotiocianato/metabolismo , Interleucina-17/toxicidad , Interleucina-17/metabolismo , Interleucina-17/uso terapéutico , Interleucina-4/toxicidad , Interleucina-4/metabolismo , Interleucina-4/uso terapéutico , Simulación del Acoplamiento Molecular , Hígado/metabolismo , Colestasis/inducido químicamente , Ácidos y Sales Biliares , Compuestos EpoxiRESUMEN
High concentrations of arsenic in soil and plant systems are a threat to human health and ecosystems. The levels of phosphate ions in the soil strongly influence the soil efficacy and arsenic absorption by plants. This study investigated the effects of phosphate-solubilizing fungi (PSF) on environmental factors and structural changes in microbial community in soils contaminated with arsenic. Four experimental groups were created: control (CK), Penicillium GYAHH-CCT186 (W186), Aspergillus AHBB-CT196 (W196), and Penicillium GYAHH-CCT186 + Aspergillus AHBB-CT196 (W186 + W196), with Pakchoi (Brassica chinensis L.) as the test plant. Analysis of altered nutrient levels, enzyme activities and microbial community structure in the soil as well as the growth and physiological characteristics of Pakchoi, revealed a significant increase in the available phosphorus (AP), organic matter (OM), cation exchange capacity (CEC) and available arsenic (AAs) content of the soil following W186 + W196, W196 and W186 treatments. All experimental treatments enhanced the activity of soil ß-glucosidase (ß-GC) and soil catalase (S-CAT). W186 + W196 and W196 treatments significantly enhanced soil acid phosphatase (S-ACP) activity. Besides, W186 + W196 treatment significantly induced dehydrogenase (S-DHA) activity. Further, of the treatment with PSF increased the fresh weight, root length, plant height and chlorophyll levels while decreasing the arsenic accumulation in Pakchoi. Exposure to PSF also increased the activity of Ascomycota, Basidiomycota, Chytridiomycota, unclassified_Fungi, Mortierellomycota, Cryptomycota and Rozellomycota in the soil. The relative abundance of Ascomycota, Basidiomycota, and Mortierellomycota was positively correlated with the available nutrients (except iron) in the soil as well as enzyme activities. Consequently, the PSF improved the quality of soil and the safety of Pakchoi, suggesting that PSF can be utilized for the remediation of arsenic-contaminated soil.
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Arsénico , Brassica , Microbiota , Contaminantes del Suelo , Humanos , Fosfatos/análisis , Arsénico/análisis , Rizosfera , Hongos , Suelo/química , Microbiología del Suelo , Contaminantes del Suelo/análisisRESUMEN
Short peptides have gained widespread utilization as functional constituents in the development of functional foods due to their remarkable biological activity. Previous investigations have established the positive influence of oysters on testosterone biosynthesis, although the underlying mechanism remains elusive. This study aims to assess the impact of three dipeptides derived from oysters on the oxidative stress state of TM3 cells induced by AAPH while concurrently examining alterations in cellular testosterone biosynthesis capacity. The investigation encompasses an analysis of reactive oxygen species (ROS) content, antioxidant enzyme activity, apoptotic status, and expression levels of crucial enzymes involved in the testosterone synthesis pathway within TM3 cells, thus evaluating the physiological activity of the three dipeptides. Additionally, molecular docking was employed to investigate the inhibitory activity of the three dipeptides against ACE. The outcomes of this study imply that the oxidative stress state of cells impedes the synthesis of testosterone by inhibiting the expression of essential proteins in the testosterone synthesis pathway. These three dipeptides derived from oysters ameliorate cellular oxidative stress by directly scavenging excess ROS or reducing ROS production rather than enhancing cellular antioxidant capacity through modulation of antioxidant enzyme activity. These findings introduce a novel avenue for developing and utilizing antioxidant peptides derived from food sources.
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Following the publication of the above paper, it was drawn to the Editor's attention by a concerned reader that a large number of data panels showing cell migration and invasion assay data in Figs. 3C and 5 contained overlapping sections, such that data that were intended to show results obtained under different experimental conditions may have been derived from a smaller number of original sources. In addition, certain of the data in this pair of figures were strikingly similar to data that were submitted for publication in another journal at around the same time as the above paper was submitted to Oncology Reports. Finally, regarding the western blotting data shown in Fig. 4B, an obvious splice in the gel strip was noticed for the FBXW7 bands, whereas no equivalent splice was present in the associated GADPH loading control, suggesting that these data originated from different gels. Owing to the fact that the contentious data in the above article were under consideration for publication at around the time that this was submitted to Oncology Reports, in addition the other features of concern regarding the data, the Editor has decided that this paper should be retracted from the Journal on account of a lack of confidence in the presented data. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [Oncology Reports 38: 30303038, 2017; DOI: 10.3892/or.2017.5995].
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The intense impulse noise may damage the soldiers' hearing organs during a weapon's firing. It is essential to find out the generation mechanism of the overpressure at the bottom of the ear. The experiments of measuring the overpressure at the bottom of the ear were conducted through a rotating human head model at a recoilless weapon firing platform. The results showed that the overpressure peak at the bottom of the ear decreases with the increasing incident angle. A simulation of the test condition was developed based on the plane shock wave method. The finite element model was verified reasonably compared to the test results. The Friedlander wave propagating to the ear canal was implemented at different incident angles. The generation of the overpressure at the bottom of the ear was analyzed. According to the pressure nephograms, the impulse noise stagnated at the bottom of the ear, so the overpressure was the total pressure of impulse noise. Two parts of impulse noise entered the canal successively due to the influence of the pinna. The overpressure and Mach number at the entrance of the ear canal both decreased with increasing incident angles, resulting in impulse noise superimposed at the bottom of the ear. Investigating the generation of overpressure at the bottom of the ear under varying incident angles may have important reference value for analyzing and preventing auditory organ damage caused by impulse noise.
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Audición , Humanos , Análisis de Elementos FinitosRESUMEN
Bacterial infections can significantly impede wound healing and pose a serious threat to the patient's life. The excessive use of antibiotics to combat bacterial infections has led to the emergence of multi-drug-resistant bacteria. Therefore, there is a pressing need for alternative approaches, such as photothermal therapy (PTT), to address this issue. In this study, for the first time, CuS NPs with photothermal properties were synthesized using sericin as a biological template, named CuS@Ser NPs. This method is simple, green, and does not produce toxic and harmful by-products. These nanoparticles were incorporated into a mixture (XK) of xanthan gum and konjac glucomannan (KGM) to obtain XK/CuS NPs composite hydrogel, which could overcome the limitations of current wound dressings. The composite hydrogel exhibited excellent mechanical flexibility, photothermal response, and biocompatibility. It also demonstrated potent antibacterial properties against both Gram-positive and negative bacteria via antibacterial experiments and accelerated wound healing in animal models. Additionally, it is proved that the hydrogel promoted tissue regeneration by stimulating collagen deposition, angiogenesis, and reducing inflammation. In summary, the XK/CuS NPs composite hydrogel presents a promising alternative for the clinical management of infected wounds, offering a new approach to promote infected wound healing.
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Infecciones Bacterianas , Hidrogeles , Animales , Hidrogeles/farmacología , Cicatrización de Heridas , Antibacterianos/farmacología , ColágenoRESUMEN
The gradient temperature was manipulated to construct hollow irregular carbon spheres with regulated intrinsic defects and surface area targeting favorable potassium storage. An enlarged surface area, increased intrinsic defects, and superior conductivity induced more surface-active interfaces. These actions facilitated a high reversible capacity as well as excellent cycling stability.
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Infantile neuroaxonal dystrophy (INAD) is a rare autosomal recessive neurodegenerative disease characterized by early hypotonia, and rapid progression to psychomotor development regression, pyramidal tract positivity, and spastic quadriplegia. In this report, we describe a Chinese patient with INAD who presented with hypotonia, delayed motor and language development, and subsequently improved with rehabilitation training. Genetic testing revealed that the patient had compound heterozygous PLA2G6 gene variants, with the heterozygous c.496dupG (p.Glu166fsTer32) variant inherited from her father and the heterozygous c.2189T>G (p.Met730Arg) variant inherited from her mother. The p.Met730Arg was a novel variant. The protein structure predicts that the structural stability of the mutant protein may change, and the in vivo experimental results show that the expression of the mutant protein decrease. This study enriches the PLA2G6 gene mutation spectrum, and improves the clinicians' diagnostic awareness of INAD.
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Distrofias Neuroaxonales , Enfermedades Neurodegenerativas , Humanos , Niño , Femenino , Enfermedades Neurodegenerativas/genética , Hipotonía Muscular/genética , Pruebas Genéticas , Mutación , Distrofias Neuroaxonales/genéticaRESUMEN
Bacterial infection is one of the most critical obstacles in wound healing, and severe bacterial infections can lead to inflammatory conditions and delay the healing process. Herein, a novel hydrogel based on polyvinyl alcohol (PVA), agar, and silk-AgNPs was prepared using a straightforward one-pot physical cross-linking method. The in situ synthesis of AgNPs in hydrogels exploited the reducibility of tyrosine (Tyr tyrosine) in silk fibroin, which endowed the hydrogels with outstanding antibacterial qualities. In addition, the strong hydrogen bond cross-linked networks of agar and the crystallites formed by PVA as the physical cross-linked double network of the hydrogel gave it excellent mechanical stability. The PVA/agar/SF-AgNPs (PASA) hydrogels exhibited excellent water absorption, porosity, and significant antibacterial effects against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). Furthermore, in vivo experimental results confirmed that the PASA hydrogel significantly promoted wound repair and skin tissue reconstruction by reducing inflammation and promoting collagen deposition. Immunofluorescence staining showed that the PASA hydrogel enhanced CD31 expression to promote angiogenesis while decreasing CD68 expression to reduce inflammation. Overall, the novel PASA hydrogel showed great potential for bacterial infection wound management.
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Infecciones Bacterianas , Alcohol Polivinílico , Humanos , Agar , Alcohol Polivinílico/química , Staphylococcus aureus , Escherichia coli , Antibacterianos/farmacología , Antibacterianos/química , Cicatrización de Heridas , Hidrogeles/farmacología , Hidrogeles/química , InflamaciónRESUMEN
The fungal taxa belonging to the Clavicipitaceae (Hypocreales, Ascomycota) are widely distributed and include diverse saprophytic, symbiotic and pathogenic species that are associated with soils, insects, plants, fungi and invertebrates. In this study, we identified two new fungal taxa belonging to the family Clavicipitaceae that were isolated from soils collected in China. Morphological characterisation and phylogenetic analyses showed that the two species belong to Pochonia (Pochoniasinensissp. nov.) and a new genus for which we propose Paraneoaraneomycesgen. nov. in Clavicipitaceae.
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Thelebolales are globally distributed fungi with diverse ecological characteristics. The classification of Thelebolales remains controversial to date and this study introduces two new taxa, based on morphological and phylogenetic analyses. The results of phylogenetic analyses indicated that the new taxa formed distinct lineages with strong support that were separated from the other members of Thelebolales. The new taxa described herein did not form sexual structures. The phylogenetic relationships of the new taxa and the morphological differences between these taxa and the other species under Thelebolales are also discussed.
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With the in-depth understanding of bone regeneration mechanisms and the development of bone tissue engineering, a variety of scaffold carrier materials with desirable physicochemical properties and biological functions have recently emerged in the field of bone regeneration. Hydrogels are being increasingly used in the field of bone regeneration and tissue engineering because of their biocompatibility, unique swelling properties, and relative ease of fabrication. Hydrogel drug delivery systems comprise cells, cytokines, an extracellular matrix, and small molecule nucleotides, which have different properties depending on their chemical or physical cross-linking. Additionally, hydrogels can be designed for different types of drug delivery for specific applications. In this paper, we summarize recent research in the field of bone regeneration using hydrogels as delivery carriers, detail the application of hydrogels in bone defect diseases and their mechanisms, and discuss future research directions of hydrogel drug delivery systems in bone tissue engineering.